Taxoid derivative and method of producing thereof
A taxoid derivative wherein sugar is combined with any one of paclitaxel, docetaxel and 10-deacetyl-bacatin III via a spacer. A method of producing the taxoid derivative comprises protecting hydroxyl groups at specific position of paclitaxel or docetaxel by protective compound followed by reacting with tetrabenzyl acetyloxyglucoside, and then carrying out debenzyl and detriethylsilyl reactions. A method of producing the taxoid derivative comprises reacting paclitaxel or docetaxel with tetrabenzyl acetyloxyglucoside, and then carrying out debenzyl reaction.
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Claims
1. A taxoid derivative wherein sugar is combined with any one of paclitaxel, docetaxel and 10-deacetyl-baccatin III via a spacer.
2. The taxoid derivative according to claim 1, wherein the sugar is a sugar selected from the group consisting of glucose, mannose, allose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, psicose, fructose, sorbose, tagatose, fucose and maltose.
3. The taxoid derivative according to claim 1, wherein the spacer is glycolate.
4. Glucosyloxyacetyl-7-paclitaxel represented by the following formula.
5. Glucosyloxyacetyl-2'-paclitaxel represented by the following formula. ##STR25##
6. Diglucosyloxyacetyl-2',7-paclitaxel represented by the following formula. ##STR26##
7. Glucosyloxyacetyl-10-paclitaxel represented by the following formula. ##STR27##
8. N-(glucosyloxyacetyl)-N-debenzoylpaclitaxel represented by the following formula. ##STR28##
9. N-(glucosyloxyacetyl)-N-debutoxycarbonyldocetaxel represented by the following formula. ##STR29##
10. Glucosyloxyacetyl-2'-docetaxel represented by the following formula. ##STR30##
11. Diglucosyloxyacetyl-2',7-docetaxel represented by the following formula. ##STR31##
12. Triglucosyloxyacetyl-2',7,10-docetaxel represented by the following formula. ##STR32##
13. Glucosyloxyacetyl-7-docetaxel represented by the following formula. ##STR33##
14. Diglucosyloxyacetyl-7,10-docetaxel represented by the following formula. ##STR34##
15. Glucosyloxyacetyl-10-docetaxel represented by the following formula. ##STR35##
16. Glucosyloxyacetyl-10-baccatin III represented by the following formula. ##STR36##
17. A method of producing a taxoid derivative of claim 4, 13 or 14, comprises protecting a hydroxyl group at the 2' position of a paclitaxel or docetaxel by chlorotriethylsilane followed by reacting said paclitaxel or docetaxel with tetrabenzyl acetyloxyglucoside represented by the following formula and then, carrying out debenzyl and detriethylsilyl reactions. ##STR37##
18. A method of producing a taxoid derivative of any one of claims 5, 6, 10, 11 and 12, comprises reacting paclitaxel or docetaxel with tetrabenzyl acetyloxyglucoside represented by the following formula and then, by carrying out a debenzyl reaction. ##STR38##
19. A method of producing a taxoid derivative of claim 15, comprises protecting hydroxyl groups at the 2' and 7 positions of docetaxel by triethylsilyl groups followed by reacting said docetaxel with tetrabenzyl acetyloxyglucoside represented by the following formula and then, carrying out debenzyl and detriethylsilyl reactions. ##STR39##
20. A method of producing a taxoid derivative of claim 7, comprises protecting hydroxyl groups at the 2' and 7 positions of 10-deacetylpaclitaxel by a triethylsilyl group, reacting said 10-deacetylpaclitaxel with tetrabenzyl acetyloxyglucoside represented by the following formula and then, carrying out debenzyl and detriethylsilyl reactions. ##STR40##
21. A method of producing a taxoid derivative of claim 16, comprises protecting hydroxyl groups at the 7 position of 10-deacetyl-baccatin III by a triethylsilyl group, reacting said 10-deacetylpaclitaxel with tetrabenzyl acetyloxyglucoside represented by the following formula and then, carrying out debenzyl and detriethylsilyl reactions. ##STR41##
| WO 94/18954 | September 1994 | WOX |
| WO 96/11683 | April 1996 | WOX |
- N. Palma, et al., Eur. Congr. Biotechnol., vol. 1, pp. 533-542, 1984, "Pleurmutilin Related Metabolites Produced By Submerged Culture Of The Basidiomycetous Genus Clitopilus Kummer". Dreis B.A. De Bont, et al., Bioorganic & Medicinal Chemistry, vol. 5, No. 2, pp. 405-414, Feb. 1997, "Synthesis and Biological Activity of .beta.-Glucuronyl Carbamate-Based Prodrugs Of Paclitaxel as Potential Candidates for Adept". Koppaka V. Rao J. Heterocyclic Chem., vol. 34, No. 2, pp. 675-680, Mar. 1997, "Semi-Synthesis of Paclitaxel from Naturally Occurring Glycosidic Precursors".
Type: Grant
Filed: Jun 3, 1997
Date of Patent: Jun 16, 1998
Assignees: Ensuiko Sugar Refining Co., Ltd. (Yokohama), Tadakatsu MANDAI (Kurashiki), Kaken Pharmaceutical Co., Ltd. (Tokyo)
Inventors: Tadakatsu Mandai (Kurashiki), Hiroshi Okumoto (Kurashiki), Koji Hara (Yokohama), Katsuhiko Mikuni (Yokohama), Kozo Hara (Yokohama), Hiroki Hamada (Okayama)
Primary Examiner: Ba K. Trinh
Law Firm: Oblon, Spivak, McClelland, Maier & Neustadt, P.C.
Application Number: 8/868,151
International Classification: C07D30514;
